6, 19-lactones of 4, 5-dehydro-10-carboxy-6beta-hydroxy-3-oxo steroids and process for the preparation thereof



United States Patent 3,210,343 6,19 -LACTONES OF 4,5-DEHYDRO--CARBOXY- 6,8-HYDROXY-3-OXO STEROIDS AND PROCESS FOR THE PREPARATION THEREOF Derek Harold Richard Barton, Cambridge, Mass, assignor to Research Institute for Medicine and Chemistry, Cambridge, Mass., a corporation of Massachusetts No Drawing. Filed Dec. 3, 1962, Ser. No. 241,479 Claims priority, application Great Britain, Dec. 5, 1961, 43,518/61 16 Claims. (Cl. 260-23957) This invention is concerned with the production of l9-nor-3-oxo-4,5-dehydro steroids and novel intermediates of use in such production.

19-nor3-oxo-4,5-dehydro steroids have in recent years become of interest in pharmacology. Thus, for example, the compound 17a ethinyl 17 8 hydroxy-19-nor-A androsten-B-one has proved of especial use in oral contraception and other 19-n0r-steroids have been shown to possess useful anabolic, anti-fertility and progestational action. Previous methods of synthesising such compounds have, however been diflicult to carry out in practice. It has now been found that these 19-nor-steroids can conveniently be prepared by reduction of the lactones of the corresponding 19-carboxy-6fi-hydroxy-steroids with metal or metal ion reducing systems, that is with reducing systems in which a metal is dissolving in an aqueous or acid medium or in which metal ions in a low valency state are converted to a higher valency state. In this process the bonds linking the lO-position and 6-position carbon atoms to the lactone oxycarbonyl group are broken so that no substituents remain at these carbon atoms.

According to the present invention therefore there is provided a process for the production of 4,5-dehydro-3- oxo-19-nor-steroids in which the lactone of a 4,5-dehydro-IO-carboxy 6B hydroxy 3 oxo steroid is reduced with a reducing system selected from the group consisting of dissolving metal and low-valency metal ion reducing systems, whereby the substitution at the 6- and 10-positions is removed.

The reducing system may, for example, be zinc in the presence of acid, for example, a mineral acid such as aqueous hydrochloric, hydrobromic, sulphuric acid, etc., or, preferably, an organic acid such as glacial or aqueous alkanoic acid, e.g., acetic acid or propionic acid. The zinc is preferably in dust form but may also be in the form of a copper zinc couple. Other reducing metals include, for example, tin, aluminium, amalgam, etc. The reducing agent may also comprise a compound furnishing metal ions in a low valency state which are capable of being easily oxidised to a higher valency state, for example, titanous, chromous or stannous salts, e.g., the chlorides.

The reduction may be effected in a solvent medium, metal ion reducing agents being more eifective in aqueous media. Where zinc dust and glacial alkanoic acid are used, the acid may also serve as reaction medium.

The steroid lactone starting material will in general carry substituents at other positions in the molecule, for example a keto group at the IL and/or 17-position, a methyl group at the 6- or 16-positions, a halogen atom at the 9-position, for example, a fluorine atom, a hydroxy 31,210,343 Patented Oct. 5, 1965 group, acetyl or 1,5-dimethyl hexyl group at the 17-position, etc. A -keto group of the 17-positi'on is preferred since the resulting 19-nor steroid may then be converted into, for example, a l7a-ethinyl-l7fi-hydroxy compound such as the 17-a-ethinyl-17fi-hydroxy-19-nor-A -androsten- 3-one referred to above.

The lactone starting material may be prepared, for example, from a corresponding 19-carboxy-6B-hydroxy- 3-oxo-steroid lactone which carries a Sa-substituent capable of undergoing ii-elimination. The following reaction diagram indicates the configuration of the A and B rings of the steroid molecules concerned and various stages in the synthesis of these compounds by a preferred sequence of reactions.

(iii) 0 0 II I f o i o:

(vii) (viii) In the above reaction diagram, X represents a ,8- eliminatable substituent, for example, a halogen atom, such as a fluorine, chlorine, bromine or iodine atom or 3 a hydroxyl or sulphonyloxy group, e.g., a methansulphonyloxy or toluensulphonyloxy group, etc. R represents a group which may be converted into a keto group, for example, an acyloxy group which can be hydrolysed to hydroxyl and the latter oxidised to a keto group, or a protected keto group such as a ketal or thioketal group.

In converting compounds having structure (vii) into compounds of structure (viii) the presence of the x0- group in the 3-position directs the double-bond so formed into the 4,5-position. Where the substituent to be eliminated (together with a hydrogen atom at the 4-position) is a halogen atom or sulphonyloxy group, the elimination is preferably acid catalysed, for example, by mineral acid such as a hydrohalic acid, e.g., hydrogen chloride in methanol or acetic acid. Where the 5a-substitutent is a hydroxy group, elimination is preferably effected in the presence of a dehydrating agent such as phosphorus oxychloride, etc., or by heating.

Where the Soc-SllhS'tltllCIlt is easily eilminated in the presence of acid, it is often possible to omit elimination as a separate step and to react the Soc-substituted lactone having the structure (vii) directly with a metal or metal ion reducing system in the presence of acid. Thus, where a 5a-bromo-lactone is used, treatment with zinc and acetic acid effects simultaneous reduction and elimination.

The Six-substituted 3-oxo-lactone having the partial structure (vii) may be prepared from a corresponding SOC-SUbStitllt6d 19-carboxy-6fi-hydroxy steroid laetone having the partial structure (vi). As indicated above, the group R at the 3-position is a group convertible to a keto group, for example, an acyloxy group or a protected ketone group such as a ketal or thioketal group.

Where the group R is an acyloxy group, e.g., an acetoxy, propionyloxy, benzoyloxy group, etc., this may be hydrolysed to give a hydroxyl group, for example, with a mineral acid, e.g., a hydrogen halide such as hydrogen chloride etc. or sulphuric acid, or with alkali, e.g., an alkali metal hydroxide, alkoxide, etc., preferably in an aqueous organic solvent medium, e.g., aqueous dioxan, and the hydroxy group may then be oxidised to give a keto group. This oxidation may be effected, for example, by reagents suitable for oxidising secondary alcohols to keto groups. Chromium trioxide is preferred, advantageously in the presence of acetic acid, pyridine, or preferably, acetone (Jones oxidation). It is generally found, however, that the oxidation conditions may lead to simultaneous elimination of the Sa-substituent to give a mixture of saturated and unsaturated 3-oxo-steroids. Such a mixture may then be treated separately to eliminate the 5oc-substituent or may often be subjected to the final reduction step directly.

The removal of the protecting group from the protected 3-oxo-steroid, for example, a 3-ketal or 3-thio ketal of the desired compound, may be eifected by hydrolysis, for example, with a mineral acid, e.g., hydrochloric acid, sulphuric acid etc.

The S-substituted l9-carboxy-6-hydroxy steroid lactone having the partial structure (vi) may be prepared by oxidation of the corresponding 5-substituted 6,19-hemiacetal, having the partial structure (v), for example by chromium trioxide oxidising agents such as Jones reagent (chromium trioxide in acetone). The hemiacetal may conveniently be prepared from the corresponding S-substituted 6-hydroxy-steroid oxime having the partial structure (iv) by cleavage to the aldehyde which then forms the desired hemiacetal with the 6-position hydroxyl group. The cleavage of the oxime may be etfected by aqueous acid, e.g., mineral acid such as hydrochloric, sulphuric acid, etc., or, advantageously, by nitrous acid, for example, by reaction with a nitrite in the presence of acid.

The oxime of partial structure (iv) may be prepared, for example, by photolysis of a nitrite ester having the partial structure (iii). The nitrite ester may be irradiated with ultra-violet light at a wavelength corresponding to the absorption maximum of the nitrite radical, i.e.,

4 between about 3000 and 4400 A. preferably between 3400 and 4000 A. The irradiation of the desired wavelength may be supplied by a high pressure mercury arc lamp. The irradiation is preferably etfected in dilute solution, conveniently in a solvent having low absorption at the wavelengths used, e.g., hydrocarbons such as benzene, toluene, chlorinated hydrocarbons, e.g., carbon tetrachloride, chloroform, etc. The initial photolysis product is a nitroso derivative which is normally dimeric but this may be readily isomerised to give the desired oxime under prototropic conditions, e.g., by heating in an inert solvent.

The nitrite ester having the partial structure (iii) may be prepared, for example, by reacting a 6-hydroxy steroid having the partial structure (ii) with a nitrosylating agent such as a nitrosyl halide, e.g., nitrosyl chloride. Nitrosyl halides are preferably reacted with a solution of the 6- hydroxy steroid containing a base as hydrogen halide acceptor, e.g., an organic base such as pyridine, N-methyl piperidine, triethylamine etc.

The 6-hydroxy steroid of partial structure (ii) where X is halogen may be obtained, for example, by reaction of a 5,6-dehydro-steroid having the partial structure (i) with a hypohalous acid. Thus, the preferred compounds having the partial structure (ii) where X is bromine may be obtained by reacting the 5,6-dehydro steroid with hypobromous acid. The hypobromous acid may, for example, be generated in situ using an N-bromoamide or imide such as N-bromoacetamide and acid, e.g., mineral acid such as hydrochloric or sulphuric acid or, preferably, perchloric acid. Where X is a hydroxyl or acyloxy group, the desired intermediate of partial structure (ii) may be obtained from the corresponding 5,6-epoxide by reaction with water or an appropriate acid.

It will thus be seen that the reactions described above allow useful 19-nor-steroids to be prepared from such known compounds as the B-substituted 5,6-dehydro steroids of partial structure (i) and the present invention includes the preparation of 19-nor steroids having the partial structure (ix) starting from 5,6-dehydro-steroids of partial structure (i) or from any of the intermediates having the partial structures (ii) to (viii). Steroids having the partial structures (ii) to (viii) have not previously been reported and constitute a further feature of the invention.

The activity of the l9-nor-3-oxo-4,5-dehydro steroids varies largely with the nature of the groups at the 17- position. Thus, for example, 17.}3-ethinyl, 17B-hydroxy 1-9-nor-A -androsten-3-one is a useful oral contraceptive while l9-nor testosterone and its 17-acetate are useful anabolic agents; l9-nor progesterone and l9-nor-17-acetoxy progesterone are useful progestational agents.

It should be noted that the intermediates of partial structure (ii) are also of use in the synthesis of 19- hydroxy steroids.

The physiological activity of the l9-hydroxy steroids is found to vary with the substitution at the C-17 position and in general they have similar activity to the corresponding 19-nor compound. Especially useful compounds are 19-hydroxy testosterone and its 17-acetate which exert an anabolic action, l9-hydnoxy progesterone and l9-hydroxy-17-acetoxy-progesterone which exert a progestational action and l9-hydroxy cholesterol which has a blood-cholesterol lowering effect. All these compounds are new and constitute a further feature of the mventi'on.

Oxidation of the compound of skeletal structure (ii) to form a 6,19-oxide bridge, for example using lead tetraacetate, HgO and iodine, etc., yields besides oxidation products, a cyclic 6,19-ether having the partial structure where X and R have the above meanings. After isolation, e.g., by chromatography, this ether may be subjected to hydrolysis, preferably using basic conditions for example an alkali metal hydroxide, advantageously in alkanolic solution, e.g., methanolic KOH. Where R is an acyloxy group, hydrolysis yields a S-hydroxy steroid ((x), -R=OH) which may be subjected to oxidation to convert the 3-hydroxyl group into a keto group. Oxidation may be effected, for example, by Oppenauer reagents, e.g., a ketone such as acetone or acetophenone and a metal t-butoxide, e.g., alkali metal or aluminium t-butoxide, or by chromium trioxide oxidation preferably using acetone as reaction medium. The resulting 3-ketosteroid ((x), R=O=) then eliminates hydrogen halide to yield a conjugated 3-keto-4,S-dehydrosteroid. Elimination generally occurs spontaneously during oxidation but may be effected by acid catalysis. The resulting steroid having the partial structure HOCH:

It is also possible to avoid completing the elimination before reduction where the reduction conditions are acid, e.g., when using zinc and acetic acid, the preferred reducing system.

The oxidation of the 6,6-hydroxy-steroid to form a 6, l9-oxide is advantageously effected with a reagent system generating positive chlorine, bromine or iodine ions; substances generating 1+ ions are especially preferred. Thus, for example, heavy metal oxides such as mercuric, silver or plumbic oxide in the presence of I are especially efiective in closing the oxide ring and acylates of lead or metals of the 1st and 2nd sub-groups of the periodic table are also effective in the presence of I for example, acetates, propionates, benzoates, e.g., silver or mercury acetate, lead tetra-acetate, etc. Other substances which may be used to close the 6,19-oxide ring include cyanogen chloride, bromide and iodide and interhalogen compounds such as iodine monochloride or iodine monobromide.

In order that the invention may be well understood we give the following examples by Way of illustration only. All temperatures are in degrees centigrade.

Example 1.5a-br0m0-35-ncet0xy-ch0lestan-6/3-0l A solution of cholesteryl acetate (50 g.) in purified dioxan (400 cc.) and aqueous perchloric acid (23 cc., 0.5 N) was vigorously stirred in a dark flask at room temperature. N-bromoacetamide (43.2 g.) was then added to it in four portions during a period of 30 minutes. Stirring was continued for 30 minutes after the last addition. The reaction mixture, after being cooled in icewater, was diluted with water (200 cc.) and then decomposed with aqueous sodium sulphite (300 cc.). The product was extracted with ether and the organic layer was washed with water, dried (Na SO and evaporated. Crystallization from methylene chloride-hexane gave 5abromo-3[3-acetoxy-cholestan-6/3-o1 (344 g.; 61%), M.P.

11$; 3600 ms, 1725 s. cm.-

6 Example 2.5a-brom0-3B-acet0xy-andr0stan- 6,8-0l-17-0ne A solution of 3B-acetoxy-androsten-17-one (20 g.) in purified dioxan (160 cc.) and aqueous perchloric acid (9.2 cc., 0.5 N) was treated with N-bromoacetamide (17.3 g.) as described in the preceding experiment. After being extracted with methylene chloride, the product was worked up as usual. Crystallization from hexane yielded 5abromo 3B acetoxy androstan 6,8-01-17-one (19.2 g., 74.7%). An analytical sample was crystallized from methanol and had M.P. 171172, [M +1.9 (CHCl c.=1.19)

vii, 3650 ms, 1740 s. cm.-

(Found: C, 58.65; H, 7.45; O, 15.00; Br, 19.05. C H O Br requires: C, 59.00; H, 7.30; O, 14.95; Br, 18.75%.)

Example 3 .5 Ot-bl'OmO-3 ,8,1 7 B-diacet0xy-andr0stan-6 ,B-ol

A solution of 3B,17fi-diacetoxy-androstene (30 g.) in purified dioxan (240 cc.) and aqueous perchloric acid (13.8 cc., 0.5 N) was treated with N-bromoacetamide (25.92 g.) as described in the preceding experiment. After being extracted with methylene chloride, the product was worked up as usual. Crystallization from acetone-hexane gave 5ot-bromo-3B,17fi-diacetoxy-androstan-6B-ol (21 g., 56%), M.P. 168172. Recrystallization from methylene chloride-hexane gave M.P. 170172.5, [a] -49 (CHCl c.=1.09). (Found: C, 58.50; H, 7.25; Br, 16.25. C H O Br requires: C, 58.60; H, 7.50; Br, 16.95%.)

Example 4 .-5 a-br0mo-3 ,B-acetoxy-cholestan-6 ,B-yl nitrite A solution of 5u-bromo-3fi-acetoxy-cholestan-66-01 (25 g.) in dry pyridine (300 cc.; Karl Fischer reagent) was treated with nitrosyl chloride at 20 until a blue colour appeared. The reaction mixture was decomposed by a slow addition of ice-water (500 cc.) and the resulting precipitate was filtered and washed with water. The product was then taken in a minimum amount of methylene chloride, dried (Na SO and crystallised by the addition of methanol to yield 5a-bromo-3fl-acetoxy-cholestan-6B- yl nitrite (22.4 g.; M.P. -112, [041 -70 (CHCl c=0.965)

1750 s., 1660 va. CHI-1 (Found; C, 62.45; H, 8.40; N, 2.55; Br, 14.60.

c rn onarN requires: C, 62.80; H, 8.70; N, 2.55, Br, 14.40%.)

A solution of the above nitrite in toluene (700 cc.) was irradiated in a standard apparatus with a 200 watt high pressure mercury lamp at 0. After three hours the nitroso dimer was filtered off, washed with hexane, taken in isopro-panol (300 cc.) and heated on a steam bath for two minutes beyond the disappearance of the green colour. Removal of the solvent in vacuo and crystallisation of the residue from methanol gave 5ot-bromo-3B- acetoxy-19-oximino-cholestan-6B-ol (16 g., 55%), M.P. 176480", [M 35 (CHCl c.=0.864). (Found: C, 62.75; H, 8.75; N, 2.45; Br, 14.30. C H O BrN requires: C, 62.80; H, 8.10; N, 2.50; Br, 14.40%.)

A solution of 5a-bromo-3p,17B-diacetoxy-androstan- 613-01 (9.83 g.) in pyridine (200 cc.) was treated with gaseous nitrosyl chloride at 10 until a blue colour appeared. The reaction mixture was then decomposed with cold water and the resulting oily mixture chilled until it turned into a solid. The solid was filtered, washed free of pyridine, dissolved in ether, filtered through sodium sulphate and evaporated to dryness under vacuum.

Example 7.Pht0lysis of Son-bromo-SBJ7B-diacel0xyandrostan-o-yl nitrite v,,,,., 360 ms, 1745 s. 1720 s. GEL-1 (Found: C, 54.90; H, 6.90; N, 2.75; Br, 16.20.

C H o NBr requires: C, 55.20; H, 6.85; N, 2.80; Br, 15.96%.)

Example 8 .Preparation and photolysis of m-bromo- 3 B-acetoxy-androstan-l 7-one-6/3-yl nitrite A solution of 5a-bromo-3B-acetoxy-androstan-6 8-ol- 17-one (20 g.) in pyridine (400 cc.) was treated with nitrosyl chloride at 30 until a blue colour appeared. The reaction mixture was decomposed by a slow addition of cold water and the resulting crystalline precipitate filtered and washed several times with water to remove the last traces of pyridine. The crystalline precipitate was dissolved in toluene (600 cc.), filtered through sodiurn sulphate and irradiated at 0" using a 500 watt high pressure mercury lamp. After one hour, the insoluble nitroso dimer (8.65 g.) was filtered oil.

The preceding nitroso dimer (8.65 g.) in isopropanol (200 cc.) was heated on the steam bath for two minutes beyond the disappearance of the green colour. Evaporation of the solvent under vacuum and crystallisation from acetone/hexane gave 5a-hromo- 3 3-acetoxy-l9-oximinoandrostan-6B-ol-17-one (7.65 g.). An analytical sample crystallised from acetone-hexane had M.P. 178.5180, 11 (dioxan, c.=0.445)

1 340 vs. (broad), 1750 vs., 1700 (shoulder) cm.

(Found: C, 55.15; H, 6.65; O, 17.45; N, 3.00. C H O N requires: C, 55.25; H, 5.65; O, 17.55, N, 3.05%.)

Example 9.5o-br0mo-3;8-acetoxy-ofl-hydroxy-cholestan 19-oic lactone A solution of the oxime prepared in Example 5 (5 g.) in glacial acetic acid (850 cc.) and water (170 cc.) at 70 was treated with sodium nitrite (5 g.). After 2 minutes the reaction mixture was poured into ice-l-H O and extracted several times with methylene chloride. The organic layer was worked up as usual. The residue, without any further purification, was used for oxidation.

The preceding oil (ca. 5 g.) in acetone (250 cc.) was treated with an excess of Jones reagent at room temperature for 3 minutes, then with methanol and water. The product was extracted with ether and worked up as usual. The residue was chromatographed on alumina (250 g.) and fractions were eluted with hexane containing increasing amounts of benzene. The less polar fractions on crystallisation from methanol gave 5u-bromo-3B-acetoxy- 6B-hydroxy-cholestan 19 oic lactone (1.9 g.; 32%), M.P. l70172, 16.2 (CHCl ,c.=-1.05)

7E5; 1775 vs., 1735 cmf (Found: C, 64.95; H, 8.35; Br, 14.75. C H O Br requires: C, 64.80; H, 8.45; Br, 14.75%.) While the later fractions on crystallisation from methanol gave 50- brorno-3B-acetoxy-19-oxo-cholestane, 6,19 hemiacetal acetate (900 mg, 16%), M.P. l39-142, recrystallisation v19-0ic lactone mg,

8. from aqueous acetic acid gave the pure diacetate, M.P. 151-156", [u] +20.6 (CHCl c.=1.1)

115. 1740 vs., cmf

(Found: C, 64.25; H, 8.50;O, 13.85;Br, 13.90.

requires: C, 64.00; H, 8.50; O, 13.75; Br, 13.75%.)

Example 10.5a-br0mo-3l3-acel0xy-6B-hydr0xyl 9-oxo-andr0stan-1 7-0ne 6,19 hemiacera-l A solution of the oxime prepared in Example 8 (2 g.) in acetic acid cc.) and water (20 c.) was treated with sodium nitrite (2 g.) at 70 for 3 minutes. The reaction mixture was cooled, diluted with aqueous sodium chloride, extracted several times with methylene chloride and worked up as usual. Chromatography of the residue on alumina (60 g.), and elution of fractions with hexane containing increasing amounts of benzene gave, after crystallisation of the solid fraction from methylene chloride/hexane, Sa-bromo 3B-acetoxy 6,8-hydroxy-19-oxoandrostan-17-one 6,19 hemiacetal (270 mg). Recrystallisation from ether/ petroleum ether gave plates mp. 184-186", [a] "+41 (CHCl c.-=l.04).

v5.1, 3600 s., 1740 vs., 1700 vs. cmf

(Found: C, 56.85; H, 6.45; O, 17.75; Br, 18.10. C H O Br requires: C, 57.15; H, 6.60; O, 18.10; Br,

Example 1 1 .-5u-bromo63-1102t0xy-6/3-hydr0xyandr0stan-19-0ic lactone A solution of the oxime prepared in Example 8 (9.3 g.) in acetic acid (500 cc.) and water (100 cc.) was treated with sodium nitrite (9.3 g.) as described in the previous experiment. The crude hemiacetal in acetone (200 cc.) was treated with an excess of Jones reagent at room temperature for 3 minutes, then with methanol and water. The product was extracted with ether and worked up as usual. crystallisation of the residue from methylene chloride/hexane gave 5a-bromo-3fi-acetoxy-GB-hydroxy-androstan-19-oic lactone (2.35 g.). Chromatography of the mother liquors on alumina (80 g.) and elution of fractions with hexane containing increasing amounts of benzene gave, after crystallisation of the less polar fractions, the desired lactone (2.9 g.) (total yield 59%). The more polar fractions after crystallisation yielded the hemiacetal diacetate (ca. 1.2 g.) which could not be obtained analytically pure. The desired lactone, on recrystallisation from methylene chloride-hexane, had M.P. 221-229", [a] 13 (CHCl c.'=1.03)

?; 1780 vs., 1750 vs., 1240 vs. cmi

(Found: C, 57.10; H, 6.05; Br, 18.05. C H O Br requires: C, 57.40; H, 6.20; Br, 18.20%.)

Example 12.5u-br0m0-3B-6B-dihydr0xych0lestan-19-oic lactone ture, the reaction mixture was heated on a steam bath for 2 hours, cooled, diluted with water, extracted with ether and worked up as usual. crystallisation from acetone/hexane gave 5a-bromo-3 8,65-dihydroxy-cholestam 73%) M.P. 173.5l78.5, [oc] 17.9 (C111 c.=0.89).

3450 ms., 1780 vs. cm?

rnax.

' methylene chloride and worked up as usual.

Example 1 3 .5 a-brom -3 6,6;8-(11' hydroxy-androstan- 17-0n-19-0ic lactone 3500 s., 1775 vs., 1725 vs. (broad) tam max.

(Found: C, 57.65; H, 6.50; O, 16.20; Br, 19.85. C H O Br requires: C, 57.45; H, 6.35; O, 16.10; Br,

Example 14.5x-br0m0 6fl-hydroxy-cholestan-3-0n-19- oic lactone and A -6B-hydr0xy-ch0Iestan-3-0n-19-0ic lactone A solution of the hydroxy lactone, prepared in Example 12 by hydrolysis of the acetoxy lactone, (340 mg), in acetone (25 cc.) was treated with an excess of Jones reagent, then with methanol and water. The reaction mixture was extracted with ether and worked up as usual. crystallisation from methanol gave the bromo ketone (175 mg.) M.P. 176-181, [a] +19.4 (CHCI c.=0.875).

vii; 1775 vs., 1730 ms. em."

(The ketone decomposes 0n attempted recrystallisation.)

A solution of preceding bromo ketone (100 mg.) in acetic acid cc.) containing a drop of hydrochloric acid was heated on a steam bath for 10 minutes and then worked up to yield A -6B-hydroxy-cholestan-3-on-19- 01C lactone M.P. 179-184", [a] +102 01101,, c.=0.976),

xg g f 238 m (s.=12,500) 935 1775 vs., 1660 vs.

(Found: C, H, O, C27H4003 requires: C, 78.6; H, 9.75; O, 11.65%.)

Example 15.19-n0r-ch0lesten0ne (12 cc.; 1.2 N) and the mixture refluxed for 15 minutes.

After being diluted with water, the reaction mixture was Worked up as usual. The residue was chromatographed on alumina (30 g.) and fractions eluted with hexane containing increasing amounts of benzene. The fractions showing only a conjugated ketone band (1660 cmf were combined with sublimed (200/ 1 mm.) to yield 19-nor-cholestenone (225 mg.; 47% overall yield) [a] +44.2 (CHCl c.=1.05)

A??? 240 =14,000 @39 1665 vs., 1610 w. crnf (Found: C, 83.45; H, 11.80; 0, 4.60. C H O requires C, 84.25; H, 11.40; 0, 4.30%).

Example 16.-A -6,B-hydroxy-androstene- 3,1 7 -di0ne-1 9-0ic lactone A solution of the hydroxy lactone prepared in Example 13 (200 mg.) in acetone (20 cc.) was treated with an excess of Jones reagent (1 cc.) at room temperature for 4 minutes, and then with methanol and water. The reaction mixture was extracted with ether and worked Zinc was removed by up as usual. The residue was taken in chloroform (20 cc.) and meth'anolic hydrochloric acid (2 cc.; 0.8 N) and refluxed for 15 minutes. Dilution with water, extraction with methylene chloride followed by crystallisation from methylene chloride-hexane gave A -6fi-hydroxy-androstene-3,,17-dione-19-oic lactone mg., 65%). The analytical sample was crystallised from ether-petroleum ether and had M.P. 291-293", [a] 86 (CHCl c.=0.995).

235 ma (e=12,000)

(Found: c, 72.45; H, 7.05; 0, 20.50. c H o, requires: C, 72.60; H, 7.05; O, 20.35%).

Example 17.19-110r-A -androstene-3J7-di0ne In subsequent reactions, the isolation of the unsaturated ketone prepared in Example 16 was not deemed necessary. Instead, the hydroxy lactone starting material (290 mg.) was oxidized as previously described to give a mixture of desired conjugated and unconjugated ketones. This was then taken in acetic acid (28 cc.) boiled with gentle stirring, and treated with zinc duct (4.8 g.) in two portions over a period of 15 minutes. The inorganic material was removed by filtration and the acetic acid evaporated under vacuum. The product was extracted with chloroform and worked up as usual. The residue was dissolved in chloroform (10 cc.) and methanolic hydrochloric acid (1 cc.; 0.8 N) and refluxed for 15 minutes. After being worked up as usual, the product was chromatographed on alumina. crystallisation of the solid fractions from ether-petroleum ether gave 19-nor- A4-androstene-3,17-dione (140 mg., 70%) M.P. 164- 169, [a] +136 (CHC1 c.=1.01)

AXE? 241 m (617,000) 1740 vs., 1620 s. cm.- (Found: C, 79.25; H, 8.65; O, 12.25. C H O requires: C, 79.35; H, 8.90; O, 11.75%.) Hyiura, Noguchi & Nishihawa (Chem. & Pharm. Bull., 1960, 8, 84) give M.P. 169-171", [a] (CHCl k 238 m (e=17,000)

A solution of the bromohydrin prepared in Example 2 10 g.) in benzene (600 cc.) was treated with lead tetraacetate (25 g. which had been washed with acetic acid and dried by azeotropic distillation over benzene) and refluxed overnight. After being cooled, the reaction mixture was treated with aqueous potassium iodide (60 g.) in water (1000 cc.) and extracted with ether. The combined organic extract was washed with 10% sodium thiosulphate and water respectively, dried (Na SO and evaporated. Chromatography of the resulting oil on alumina (500 g.) gave, from solid fractions after crystallisation from methanol, the desired 6,19-ether (2.9 g., 29%) M.P. 177-178", [a] +35.9 (CHCl c.= 0.715). (Found: C, 58.85; H, 7.20; O, 14.75; Br, 18.75. C H O Br requires: C, 59.30; H, 6.85; O, 15.05; Br, 18.80%.)

Example 1 9.5 a-br0m0-3 {3-1 75-diacet0xy-andr0stan- 6,19-ether The bromohydrin, Set-bromo 35,17 3 diacetoxy-6-hydroxy-androstane (5 g.) was dissolved in anhydrous benzene (250 ml.) and treated with Pb(OAc) (-15 g.) (previously washed with acetic acid and dried overnight in a vacuum desiccator containing KOH and CaCl and I (8.58 g.). The mixture was photolysed for six hours using the 200 watt lamp and with constant stirring at reflux temperature. The mixture was cooled, water was added, and the mixture was extracted with ether. The extract was washed with 10% aq. Na SO solution and water, dried, and evaporated to dryness. Residue crystallised from methanol, yield 3.435 g. (63%), M.P. 173 178 C. Analytical sample (repeat) crystallised from 1 1 ether-pet. ether, M.P. 179-181 C., [a] -7 (CHCl c.=0.720), IR 6108.

AnalysisCalcd. for C H O Br: C, 58.85; H, 7.09; O, 17.04; Br, 17.02. (M.W. 469.433). Found: C, 58.91; 'H, 6.69; O, 16.92; Br, 17.03.

Example 20.5 a-brom -3 pace toxypregn an-ZO-one- 6,19-ether The bromohydrin a-br0mo-6B- hydroxy- 3/3-acet0xypregnan-ZO-one (5 g.) in benzene (250 cc.), Pb(OAc) (9.7 g.), and 1 (5.58 g.), as described above, gave the desired ether (2.09 g.), M.P. 154157 (methanol),

[071 +56 (CHC1 c.=0.629).

Example 21 .T he preparation of 35,17a-diacet0x3 pregn-S-ene-ZO-one Steroid (50 g.) was treated with HOAc (1500 cc.), Ac O (450 cc.) and HClO [70%] (18 cc.) at 0 C. for two hours. A solid was precipitated with water, filtered, and crystallised from CH Cl -hexane. The first two crops gave 48.3 g. (87.2%) of pure diacetate, M.P. 169- 175 C. A third crop of impure product, 2.9 g. (5.2%) was obtained.

IR 115511750 vs., 1710 vs. shoulder, 1660 w. 1250 vs. cmf

Example 22.--The preparation of 3,8,17a-dz'acet0xy-5w brom0-6 8-hydroxy-pregnane-ZO-one IR 1 3500 s., 1750 vs. 1710 vs., 1700 vs., 1250 vs.,

cmr V559 3750-3500 s., 1750 vs., 1740 vs., shoulder, 1260 s., cm?

Anal. sample: [prisms from CH Cl -ether, M.P. 190- 196 C.]. C25H37O5B1 requires: C, 58.47; H, 7.26; O, 18.70; Br, 15.56. Found: C, 59.32; H, 7.43; O, 18.31; Br, 15.30. Found: C, 58.75; H, 7.24.

Example 23.T he preparation of 3,8,17a-diacet0-xy-i6fioxide pregnane-ZO-one The bromohydrin from Example 20 (l g.) was refluxed with MeOH (260 cc.) and KOAc (15 g.) for two hours. The MeOH was evaporated in vacuo and water was added. The product was filtered and crystallised from CH Cll -hexane to give a first crop of 679 mg. (80.6%).

v 1740 vs., 1710 vs., 1240 vs., 0m.-

@1101 1740 vs., 1260-1180 s., cmf

[071 20" (1.04CHCl Anal. sample [needles from CH Cl ether, M.P. 177 179 C.]. C H O requires: C, 69.42; H, 8.39; O, 22.19. Found: C, 69.34, H, 8.40; O, 22.30.

Example 24.-The preparation of 5fi,17a-diacet0xy-5achl0ro-6B-l1ydr0xypregnane-ZO-one The oxide from Example 23 (9 g.) was treated with 0.3 N CHCl -HCl (90 cc.) for 1 hour at 0 C. The

solution was washed with H O, NaHCO sat. NaCl, and

12 dried. crystallisation from CH Cl -hexane gave in two crops 9.1 g. (92.8%) of pure chl-orohydrin.

IR 112?; 3500 s., 1740 vs., 1710 vs., 1700 vs., 1260-40 vs. emi

Anal. sample [prisms from CH CI -ether, M.P. 213- 223 C.]. C H O Cl requires: C, 64.02; H, 7.95; O, 20.47; Cl, 7.56. Found: C, 64.18; H, 7.92; O, 20.21; Cl, 7.87.

Example 25.The preparation of 3,8,17u-diacet0xy-5achZ0r0-6fi,19-0xide-pregnane-20-0ne The chlorohydrin from Example 24 (1 g.) was dissolved in CCI.;( cc.) and photolyzed for 1 hour with stirring with HgO (1.8 g.) and I (2 g.). After filtration to remove the HgO, the solution was washed with N21 S O (10% aq.) and water.

crystallisation from CH CI -ether gave a first crop of 750 mg. (75.5%) of the ether.

IR r 1740 vs., 1710 vs., 1250 vs. (broad) cm.-

Anal. sample [small prisms from CH CI -ether, M.P. 183190 C. recrystallises to needle-prisms, M.P. 208- 2095 C.]. C H O Cl requires: C, 64.29; H, 7.55; O, 20.56; C], 7.59. Found: C, 64,56; H, 7.74; O, 19.90; Cl, 8.10.

Example 26. T he preparation of 3fl-hydroxy-17a-ace t0xy-5a-chlore-6B4:ydroxy-pregnane (6 19 etlzer)-20- one The product of Example 25 (1.36 g.) was treated with MeOH (100 cc.) and 5% MeOH-KOH (10 cc.) at room temperature for /2 hour. The MeOH was evaporated in vacuo, water was added, and the solid was filtered. Crystallisation from CH Cl -hexane gave a first crop of 1.02 g. (82.2%) of the hydrolysed product.

n 4:53;, 3050, 3000 s., 1740 vs., 1710 vs, 1250 vs. (ltll M1 17 (0.94CHCl Anal. sample [prisms from CH cl -ether, M.P. 225- 255 C.]. C H O Cl requires: C, 65,00; H, 7.83; O, 18.82; Cl, 8.34. Found: C, 64.86; H, 7.73; O, 18.74; Cl, 9.03.

Example 27.-The preparation 0]3' ket0-5a-chlora-6/3- hydroxy-J 7 a-acetoxy-pregnane 6- 1 9 eth er-ZO-one The crude 3 alcohol prepared by the method of Example 26 from 10 g. acetate in acetone cc.) was treated with an excess of Jones reagent for 3 min. MeOH and water were added as usual and the solid was filtered. Since this compound is unstable in boiling solvents, the ketone was not purified in this form. Crude wt.7.1 gms.

IR. 1 5, 1740 s., 1500 w. cm.-

Example 28.Tl1e preparation of 3-ket0-6fl-lzydr0xy-17aacetoxypregnl-ene (6 19 ether) 20-0ne Crude oxidation product from Example 27 (500 mg.) was treated at room temperature for 15 min. with MeOH (100 cc.) and 5% MeOH-KOH (5 cc.) After evaporation of MeOH and addition of water, the solid was filtered. Crystallisation from CH Cl -hexane gave a first crop of 242 mg. of unsaturated ketone.

Anal. sample (EtOAc-ether) 2306. (0.61CHC1;,).

IR 5. .3. 3 237 m e=14,000, V55; 1740 s., 1720 shoulder, 1665 s., 1495 W. cm.

C H O requires: C, 7.48; H, 7.82; O, 20.70. Found: C, 71.44; H, 8.02; O, 20.46.

l3 14 Example 29.The preparation of A -19-hydr0xy, 17aacetxy-pregn-3,20-di0ne I! A mixture of chloroether and o,,8 unsaturated ether prepared by the method of Example 28 (3.2 g.) in boiling R acetic acid (300 cc.) was treated with Zinc (50.4 g.) 5 added in two portions at 7 minute intervals. After 15 v min, the solution was filtered and most of the acid Was evaporated. Water was added and the solid was filtered. Chromatography yielded 220 mg. of pure 19-01.

Anal. sample (CH Cl -ether) M.P. (226) 243-245 10 A A O C. [0L]D255 +66 (0.944CHC13). c V (HI) 0 (IV) X x123 241 111,1, e=l6,300 0 OH V2,; 3600 m., 3400 ms, 7725 s., 7720 shoulder, 1660s. 15 cm? R R C H O requires: C, 71.10; H, 8.30; 0, 20,59. Found: C, 71.37; H, 8.43; O, 20.38.

A number of other compounds have been prepared by the methods of Examples 21 to 29 and the results are set out in the following table, the intermediate compounds be- 1 ing defined by reference to the following diagram: I

0 X X R 1 A 30 R HOCH R AcO- A00- I 1 II (5 H O: 0 z (VII) (VIII) Compound II III IV V (a) R=OAc M.P.168172 M.P. 139-141 M.P.195200 M.P.154158 X=Cl [Q]D2749 D -244 40. 8 D -18.4

(GHC131. 09) (CHCl3-1.03) (CHCl30 s09) (CHC130. 62) (b) R=COCH3 M.P.171174 .P.2 M.P. 131-133. 5

X=Cl D25'5+7 [(X]D27O+4Q. 5 [a]D .1 [a]D +64.9

(CHC130. 929) (CHC131. 03) (CHC130. 64) (CHC130.

[Example 19] (c) R=OAc M.P. 179-1s1 X=Br im {Emm -0 720) (d) 1 =C0OH3 M. i i:157 x=Br D ID +5G R=Octyl 11013-0. 629) (cholestan series) X=Cl Compound VI VII VIII Systematic Name of VIII (2.) R=OAc M.P.183'6" M.P.1579 M.P.165170 0. 19-h dr X=Cl [a]D +5. 9 [a] 9 [a]D 68.8 te iosi ione- (CHCI30. s5) (CHCl -1. 00) (CHC130. 799) 17 acetate. (b) =8 o0H3 iVIjP 1 16-11973 w r 142 5 M.P2.4165%68 19-hydr0xy- 04 71 (C%[c130. 583) %i1c1. I ICh progesterone ouch-1. b0 anon-o. 533 (c) R=OAe M.P. 212-215 M.P.l170 IQ-hydroxy- X Br 72) -1l68d8;g9 testosterone (d) =1C3OCH3 s 3 acetate.

r (e) R=octyl M.P. l478 (MeOH) -6 (hexane) lg-hydroxy- (chplestan vlllELX. 1, 720 cm.- max. 1, 620 cm.- cholest-4enseries) 1, 670 cur- 3-one. X= C1 3, 500 cm.-

(19 tosyl derivative) M.P.146 [a]D +9O (C=0. 10 CHCla) Calcd/Found CCCCCCCCGCGCCCCOOCCCCOOCCCCC ketal and thioketal groups and X is previously defined by a ketone oxygen atom.

Formula Yield 680 mg. (1.1 g.) C21H3 O4Cl 325 mg. (500 mg.)

Compound IIa 1.5 g. (2.0 g.)- C2aH3 O5BI- rrb 10.4 g. g.) 023H3.0l13r IIIa... 6.7 g. (10 g.) Oz3H34Os IVBI 5.0 g. (6 g.) C2aEa5O5CL IVb. 5.1 g. (6 g.) C23Ha O;C1

Va 1.5 g. (1 g.) Cz3H3sO5C1 V'b 750 mg. (l g.) CnH'uO4Cl VIa VIb.. 420 mg. 750 mg.) C21H31O;Cl

VIIa.

VIIb. 62mg. (100 mg.) CaHzaO3 VIIIa 45 mg. (100 mg.). C21H3oO4- VIIIb 50mg. (100 mg.) C21H3003- We claim: 25

1. A process for the production of 4,5-dehydro-3-oxo- 19-nor-st-eroids comprising reducing a lactone of a 4,5- 8. A process as claimed in claim 7 in which the comdehydro 1O carboxy 6,8 hydroxy 3 oxo steroid pound of the formula given in claim 7 is prepared by selected from the group consisting of the androstane, oxidation of a hemiacetal of the formula cholestane and pregnane series with a reducing system selected from the group consisting of a dissolving metal in where R and X have the meanings given in claim 7 with chromium trioxide.

2. A process as claimed in claim 1 in which the starting compound is A -6fi-hydroxy-androstem-3,17-dione-l9- oic lactone.

3. A process as claimed in claim 1 comprising the ad- A process as claimed Clair?! 8 which the hemiditional step of eliminating HX from a steroid of the ace.ta1 of formula given In clalm 8 18 prepared by reformula acting an oxime of the formula where X is selected from the group consisting of halogen, hydroxyl and hydrocarbon substituted sulphonyloxy to prepare said lactoneof said--4,5-dehydro-10-carboXy-6flhydroxy-3-oxo-steroid.

with a mineral acid.

4. A process as claimed inclaim 3 where X is selected A Process 612.1111 9 1n Whlch the OXImF from the group consisting of halogen and hydrocarbon of the formula given in claim 9 15 prepared by photolys1s substituted sulphonyloxy and the elimination is acid cata of a mtme ester 0f the formula lyzed.

5. A process as claimed in claim 3 where X is hydroxy I and the elimination is effected in' the presence of a dehydrating agent. l

6. A process as claimed in claim 3 where the elimina- PF 5 tion of HX is effected simultaneously with the reduction X (B of the lactone. N O

7. A process as claimed in claim 3 in which the starting compound of the formula given in claim 3 is prepared by Whefe X have h m g Y 1n 7 to f replacement f the group. R 5. compound f the a dime no nitroso derivative which is isomerized to give f ul the desired oxime.

11. A process as claimed in claim 10 in which the photolysis is effected with a high pressure mercury are lamp emitting ultra-violet radiation in the range 3000- 12. A process as claimed in claim 10 in which the initial nitroso dimer is isomerized by heating in an inert solvent.

Where R is selected from the class consisting of acyloxy 13. A process as claimed in claim 10 in which the said nitrite ester is prepared by reacting an alcohol of the 15. A 65 hydroxy androst-en 3,17 dione 19- formula oic lactone.

16. A compound selected from the group consisting of I a lactone of a 4,S-dehydro-10-carboXy-6fl-hydroxy-3-oxo- 5 steriod having at the l7-position a side chain selected from the group consisting of those characterizing pregnane, R g androstane and cholestane compounds.

References Cited by the Examiner where R and X have the meanings given in claim 7 with a 10 UNITED STATES PATENTS mtrosyl hallde.

14. A process as claimed in claim 13 in which the alco- 3,001,989 9/61 l f et a1 260239'55 hol of the formula given in claim 13 is prepared by react- 3,014,931 12/61 Nlshlkayva et a1 2603971 ing an unsaturated Steroid of the formula 3,067,198 12/62 Wettstern et a1 260-23955 15 3,141,016 7/64 Wettstein et a1 260-239.55

Sondheimer et al., Tetrahedron Letters N0. 22 (1960) l OTHER REFERENCES page 38 relied on.

Where R has the meaning given in claim 7 with a hypo- 20 LEWIS GOTTS, Primary Examiner. halous acid. 

15. $4-6B-HYDROXY-ANDROSTEN-3,17-DIONE-19OIC LACTONE.
 16. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A LACTONE OF A 4,5-DEHYDRO-10-CARBOXY-6B-HYDROXY-3-OXOSTERIOD HAVING AT THE 17-POSITION A SIDE CHAIN SELECTED FROM THE GROUP CONSISTING OF THOSE CHARACTERIZING PREGNANE, ANDROSTANE AND CHOLESTANE COMPOUNDS. 